Prostate Cancer Screening Jonas Hugosson Professor Avd för Urologi, Sahlgrenska Akademin, Göteborgs Universitet a) Most commonly diagnosed cancer among men worldwide, 2008 Second leading cause of Cancer death after lung cancer Source: GLOBOCAN 2008 [1] Center MM, et.al. Eur Urology 2012;61: Nationella riktlinjer för bröst-, prostata-, tjocktarmsoch ändtarmscancer Nationella riktlinjer för bröst-, prostata-, tjocktarmsoch ändtarmscancer Size at which cancer become incurable Size at which cancer is detectable Strong arguments for screening Prostate cancer kills a lot of men (2-5 % of all deaths in European men) Better health and longer life expectancy in men will immediately result in that more men will suffer and die from PC Only screen-detected cancers are curable. Those diagnosed because of symptoms are almost always too advanced for cure (Aus et al 1994, J Urol) Treatment of advanced disease only marginally improves survival and is very costly Side-effects from radical prostatectomy and radiation have decreased significantly during the last decades and in early cancers side effects are acceptable to most men. Strong arguments against screening The risk of over-diagnosis is high, approximately 50 % of screen-detected cancers will not develop symptoms during their life-time The time between screen-diagnosis and clinical symptoms (lead time) is long (mean 5-10 ys) Treatments and surveillance of PC is associated with side-effects Diagnosis of PC is associated with psychological trauma Randomised screening studies Published Number invited Weakness Stockholm Small study, one time screening, few men treated with curative intent Quebec 1999 (2004) Only 24 % participated, not evaluated according to intention to screen Norrköping Small study, not designed to evaluate mortality, PSA was included from 3rd round and only 895 men PSA tested ERSPC 2009, centers with different protocols PLCO 2009, % contamination, very low mortality in controls, low biopsy rate, no up-front power calculation Göteborg Published screening studies comparing PSA based screening with current opportunistic screening Prostate cancer mortality for individual centers Center (FU) Rate ratio (95%) Relative risk reduction P-value Netherlands (11.1 ys) 0.71 ( ) 29% Belgium (12.1 ys) 0.86 ( ) 14% NS Sweden (14 ys) 0.56 ( ) 44% Finland (11.0 ys) 0.89 ( ) 11% NS Italy (10.7 ys) 0.86 ( ) 14% NS Spain (10.7 ys) 2.15 ( ) - - Switzerland (8.2 ys) 0.89 ( ) 11% NS Conclusion of ERSPC PSA screening decreases mortality Over-diagnosis is substantial but how large is not yet established, the control group is still catching up There is a long lead-time which means that also non over-diagnosed cases will have to pay with many disease and symptoms free years. Screening is a long-term investment RR=0.56 (95% CI ) (p=0.002) NNS=293 NNT=12 EAU 2015 18-year follow up of the Gothenburg randomized population-based prostate cancer screening trial Arnsrud Godtman R, Carlsson S, Grenabo Bergdahl A, Holmberg E, Stranne J, Lilja H, Hugosson J Background: The Gothenburg screening trial has previously reported a 44% (rate ratio 0.56) relative risk reduction and a 0.4% absolute risk reduction in prostate cancer (PC) mortality after 14 years of follow up It is not clear how sociodemigraphic factors affect attendance and outcomes of an organized screening program for PC Results after 18 years PC incidence rate / 1000 person years - Screening: 9.7 (95% CI, ) - Controls: 6.5 (95% CI, ) RR 1.51 (95% CI ) PC mortality rate / 1000 person years - Screening: 0.51 (95% CI, ) - Controls: 0.79 (95% CI, ) RR 0.65 (95% CI, ) Absolute risk reduction 0.52 (95% CI ) NNI 231 NND 10 Results Attendance PC inc. rate / 1000 person yrs Rate ratio PC inc. PC mort. rate / 1000 person years Overall 77% 9.7/ / Rate ratio PC mort. Age % 77% 74% 8.7/ / / / / / Cohabitation Yes No 83% 67% 10.2/ / / / Education Low Medium/high 73% 80% 9.2/ / / / Country of origin Nordic European Non-European 78% 74% 70% 10.3/ / / / / / Comorbidity index % 73% 9.6/ / / / Conclusions At extended follow up (FU 18 years) the relative risk reduction in PC mortality decreased but the absolute risk reduction increased Men with a low level of education seem to benefit the most from organized PSA-screening An organized screening program has the potential to reduce socioeconomic inequalities in PC mortality Key Results Mortality Reduction 35 % Every man saved from PC death have an average lengthening of life with 8 years 23 % of life years gained are lost due to impaired QoL The main QoL loss is due to permanent sideeffects of treatment Number needed to treat is 5 NNI screening group = 139, NNI control group = 493 NND screening group=13, NND control group =23 Is thus PSA screening good enough for recommending all men regular testing? NO!! Why!! The risk of over-diagnosis is too high At moment all men should be informed about pros and cons and make an individual decision Can better screening decrease the risk of overdiagnosis? Mechanisms for over-diagnosis With increasing age small well differentiated cancers increases, % of men age harbour a cancer in their prostate 80 % of these cancers are small and slowgrowing and will not become clinical during life-time So how large is over-diagnosis in prostate cancer The life-time risk of being diagnosed with prostate cancer have doubled in North America and also in Scandinavia, from 8-10 % in the pre PSA era to % (Godtman et al 2012) This is accordance with simulation studies showing that almost 50 % of cancers detected with PSA testing are over-diagnosed (Steyerberg et al) Mechanisms of over-diagnosis A low specificity of PSA, only % of men in a screening situation has an elevated PSA due to a significant cancer, the remaining have other causes such as BPH, inflammation etc Current diagnostic pathway aim to biopsy the whole peripheral zone of the prostate (systematic biopsies) as PSA give no indication of where a possible cancer could be located in the gland Mechanisms of over-diagnosis Systematic blind biopsies risk to hit a small harmless cancer accidentally but also miss large cancers In the Göteborg study we estimated that each time a man undergo a systematic biopsy there is a 10 % risk of diagnosing a harmless cancer CONCLUSIONS: The postscreening PC incidence is reduced after attending three screening rounds, but not after only one or two rounds. Thus, the increased cancer detection at screening is compensated by a subsequent risk reduction only after repeated screening cycles. Distribution of Cancers detected at first screen Death from PC Clinical symptoms Fast slow Very slow Size when incurable Detectable with screening Non progressive Abnormal cell Distribution of Cancers detected at repeat screens Death from PC Fast Clinical symptoms Size when incurable Slow Very slow Detectable with screening Abnormal cell Could we improve current Screning technology Better and more specific markers, as Phi, 4K panel and the Stockholm 3 test MRI?? Hur kan diagnostiken förbättras? Is mpmri of the prostate the solution of current diagnostic problems? Is the risk of over-diagnosis decreased? What is the sensitivity of significant cancers? What is the features of these cancers missed with mpmri What is the equipment needed? 1.5 T or 3T? How large is the interobserver variation in reading the MRI? How are biopsies best guided towards MRI lesions? Prostate MRI findings with radical prostatectomy 3T MP-MRI (N=133). Lesions were identified on MRI in 126 (95%) cases. MRI showed sensitivity of 93%, PPV of 57%, and overall accuracy of 92% in predicting insignificant pathologic disease (defined as tumour volume 0.5 ml, no Gleason pattern 4) outperforming Epstein, d Amico and CAPRA criteria Turkbey Radiology. 2013 MRI of the prostate Detects 90 % of significant cancers, approximately as many as standard systematic biopsies do. Cancers less than 7-8 mm in diameter are seldom detected at MRI especially if well-differentiated MRI give an estimation of tumor size and anatomical location allowing for targeted biopsies alone Give information of stage, capsular penetration, seminal vesicle involvement Also regional lymph-glands and pelvic skeleton Göteborg 1 pilot study (Grenabo et al 2015) Cancers detected with mpmri and targeted bx in the PSA range Cancers detected with systematic bx and a normal mpmri Summary and Conclusions MRI detected % of significant cancers, appr as good as systematic biopsies MRI decreased the number of men needing biopsy with 65 % The risk of detecting harmless cancers decreased dramatically with MRI and targeted directed biopsies only compared to PSA plus systematic biopsies. MRI seemed to work as good in the PSA interval as above 3 ng/ml. If replicated in large randomised studies it would lead to a paradigm shift in diagnosing PC STUDY BASE N=40, years CONTROL SCREENING N=20,000 N=20,000 The Göteborg 2 study PSA-test & RANDOMISERING 1:1:1 ARM 1 ARM 2 ARM 3 PSA PSA + PSA PSA + PSA PSA + Reinvitation MRI Reinvitation MRI Reinvitation MRI If PSA 0.6 ng/ml 8-year interval If PSA year interval If PSA year interval If PSA year interval MRI STANDARD biopsies (TRUS 10 bx) BLINDED TO MRI RESULT No Cancer cancer Reinvitation after 2 years No cancer MRI + PLUS 4 TARGET ED bx Re-invitation after 2 years Cancer If PSA 0.6 ng/ml 8-year interval If PSA year interval If PSA year interval If PSA year interval MRI NO BIOPSIES No cancer MRI + ONLY TARGETED bx Re-invitation after 2 years Cancer If PSA 0.6 ng/ml 8-year interval If PSA year interval If PSA year interval MRI - NO BIOPSIES No cancer MRI + ONLY TARGETED bx Cancer Re-invitation after 2 years Endpoints Detection rate of significant and non significant cancers (based upon biopsy data) Will be reported in 2019/2020 Sequential screening with biomarkers followed by imaging, next step?? In future PSA (with complementary biomarkers) will be primary screening tool but with a lower threshold (1-2 ng/ml) If elevated next step is MRI If MRI is negative no biopsy but FU If MRI is positive only targeted lesion directed biopsies Screening for Cancer A balance between Benefits and Harms At the heart of the screening debate lies the ethics of information Ian S Markham. Brittish Medical Bulletin. 1998; 54 (4): p.1012.

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